rs61734621
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000069.3(CACNA1S):c.858C>T(p.Tyr286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,614,250 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 51 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 53 hom. )
Consequence
CACNA1S
NM_000069.3 synonymous
NM_000069.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.896
Genes affected
CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 1-201089300-G-A is Benign according to our data. Variant chr1-201089300-G-A is described in ClinVar as [Benign]. Clinvar id is 254854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.896 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0153 (2337/152360) while in subpopulation AFR AF= 0.0487 (2027/41582). AF 95% confidence interval is 0.047. There are 51 homozygotes in gnomad4. There are 1098 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 51 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.858C>T | p.Tyr286= | synonymous_variant | 6/44 | ENST00000362061.4 | NP_000060.2 | |
CACNA1S | XM_005245478.4 | c.858C>T | p.Tyr286= | synonymous_variant | 6/43 | XP_005245535.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1S | ENST00000362061.4 | c.858C>T | p.Tyr286= | synonymous_variant | 6/44 | 1 | NM_000069.3 | ENSP00000355192 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0153 AC: 2327AN: 152242Hom.: 50 Cov.: 32
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GnomAD3 exomes AF: 0.00534 AC: 1343AN: 251416Hom.: 26 AF XY: 0.00419 AC XY: 570AN XY: 135900
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GnomAD4 exome AF: 0.00252 AC: 3690AN: 1461890Hom.: 53 Cov.: 33 AF XY: 0.00230 AC XY: 1674AN XY: 727246
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GnomAD4 genome AF: 0.0153 AC: 2337AN: 152360Hom.: 51 Cov.: 32 AF XY: 0.0147 AC XY: 1098AN XY: 74504
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ClinVar
Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 03, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 06, 2023 | - - |
Malignant hyperthermia, susceptibility to, 5 Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 17, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Hypokalemic periodic paralysis, type 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
Congenital myopathy 18 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at